Plastic container comprising cyclic polyolefin layer

ABSTRACT

The present invention provides and a plastic container and multilayered films, which comprises a heat-sealable seal layer, a cyclic polyolefin layer, and an outermost layer, wherein the seal layer comprises polypropylene, the cyclic polyolefin layer comprises a cyclic polyolefin polymer or a cyclic polyolefin copolymer, and the outermost layer comprises a layer containing polypropylene, and which further comprises a resin composition layer comprises a blended product of a propylene polymer and a styrene elastomer. The plastic container of the present invention can suppresses a reduction in the medicament content of a liquid-state medicament and is excellent in terms of shock resistance, handling ability during the filling of the container with the medicament, and the moldability and transparency of the container.

TECHNICAL FIELD

The present invention relates to a plastic container suitable forcontaining a liquid-state medicament and a multilayered film used forthis container.

BACKGROUND ART

A reduction in the content of a certain kind of medicament is suppressedusing a container composed of cyclic polyolefin. The suppression of areduction in the content of a certain kind of medicament is disclosed inJP Patent Publication (Kokai) No. 5-293159 A (1993) (Patent Document 1)and JP Patent Publication (Kokai) No. 2003-24415 A (Patent Document 2),for example. However, cyclic polyolefin is rigid and fragile, andfurther, it is poor in terms of heat-sealing properties. Thus, cyclicpolyolefin has been problematic in that a practical bag cannot bedirectly formed with the cyclic polyolefin itself. In order to solvethis problem, JP Patent Publication (Kokai) No. 2002-301796 A (PatentDocument 3) and JP Patent Publication (Kohyo) No. 2005-525952 A (PatentDocument 4), for example, have proposed a multilayered film comprising aspecific ethylene-α-olefin copolymer and cyclic polyolefin and acontainer constituted with the same.

Moreover, if a constituted multilayered film is rigid and inflexible, itcauses problems such as low shock resistance and poor handling abilityduring the filling of a container with a medicament.

On the other hand, it has been known that a pyrazolone derivativerepresented by the formula (I) as shown below has, as a medical use, anaction to normalize brain function (Patent Document 5; JP PatentPublication (Kokoku) No. 5-31523 B (1993)), an action to suppressgeneration of lipid peroxide (Patent Document 6; JP Patent Publication(Kokoku) No. 5-35128 B (1993); the compound of Example 1), an antiulceraction (Patent Document 7; JP Patent Publication (Kokai) No. 3-215425 A(1991)), an action to suppress an increase in blood sugar (PatentDocument 8; JP Patent Publication (Kokai) No. 3-215426 A (1991)), andthe like:

(wherein R¹ represents a hydrogen atom, an aryl, an alkyl containing 1to 5 carbon atoms, or an alkoxycarbonylalkyl containing 3 to 6 carbonatoms in total; R² represents a hydrogen atom, an aryloxy, anarylmercapto, an alkyl containing 1 to 5 carbon atoms, or a hydroxyalkylcontaining 1 to 3 carbon atoms; or R¹ and R² together represent analkylene containing 3 to 5 carbon atoms; R³ represents a hydrogen atom,an alkyl containing 1 to 5 carbon atoms, a cycloalkyl containing 5 to 7carbon atoms, a hydroxyalkyl containing 1 to 3 carbon atoms, a benzyl,naphthyl or phenyl, or a phenyl substituted with 1 to 3 identical ordifferent substituents selected from the group consisting of an alkoxycontaining 1 to 5 carbon atoms, a hydroxyalkyl containing 1 to 3 carbonatoms, an alkoxycarbonyl containing 2 to 5 carbon atoms in total, analkylmercapto containing 1 to 3 carbon atoms, an alkylamino containing 1to 4 carbon atoms, a dialkylamino containing 2 to 8 carbon atoms intotal, a halogen atom, a trifluoromethyl, a carboxyl, a cyano, ahydroxyl group, a nitro, an amino, and an acetamide).

Moreover, since June 2001, the compound represented by the formula (I)has been commercially available as a brain-protecting agent (genericname: “Edaravone”; product name: “Radicut”; manufactured and distributedby Mitsubishi Tanabe Pharma Corporation). This “Edaravone” has beenreported to have high reactivity with active oxygen (Non-PatentDocuments 1 and 2). Thus, Edaravone is a free radical scavenger thatacts to scavenge various types of free radicals including active oxygenas a typical example, so as to prevent cell injury.

At present, Radicut is commercially available as a Radicut injection 30mg in the form of a 20 ml of solution containing 30 mg of3-methyl-1-phenyl-2-pyrazoline-5-one (Edaravone) filled into a glassampule. Furthermore, International Publication WO2007/55312 (PatentDocument 9) reports a plastic container filled with an aqueous solutioncontaining Edaravone, coloration of which is suppressed. However, aplastic container capable of suppressing a reduction in the content ofEdaravone due to adhesion of Edaravone to the plastic container has notyet been disclosed.

-   [Patent Document 1] JP Patent Publication (Kokai) No. 5-293159 A    (1993)-   [Patent Document 2] JP Patent Publication (Kokai) No. 2003-24415 A-   [Patent Document 3] JP Patent Publication (Kokai) No. 2002-301796 A-   [Patent Document 4] JP Patent Publication (Kohyo) No. 2005-525952 A-   [Patent Document 5] JP Patent Publication (Kokoku) No. 5-31523 B    (1993)-   [Patent Document 6] JP Patent Publication (Kokoku) No. 5-35128 B    (1993)-   [Patent Document 7] JP Patent Publication (Kokai) No. 3-215425 A    (1991)-   [Patent Document 8] JP Patent Publication (Kokai) No. 3-215426 A    (1991)-   [Non-Patent Document 1] Kawai, H., et al., J. Pharmacol. Exp. Ther.,    281(2), 921, 1997-   [Non-Patent Document 2] Wu, T W. et al., 67(19), 2387, 2000-   [Patent Document 9] International Publication WO2007/55312

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

It is an object of the present invention to provide a plastic containerwhich suppresses a reduction in the content of a liquid-state medicamentand is excellent in terms of shock resistance, handling ability duringthe filling of the container with the medicament, and the moldabilityand transparency of the container, and a multilayered film used for theaforementioned container.

Means for Solving the Problems

The multilayered film of the present invention for achieving theaforementioned object comprises a heat-sealable seal layer, a cyclicpolyolefin layer, and an outermost layer, wherein the seal layercomprises polypropylene, the cyclic polyolefin layer comprises a cyclicpolyolefin polymer or a cyclic polyolefin copolymer, and the outermostlayer comprises a layer containing polypropylene, and the presentmultilayered film further comprises a resin composition layer comprisinga blended product of a propylene polymer and a styrene elastomer.However, the multilayered film of the present invention excludes afive-layered plastic film only composed of a seal layer-an adhesivelayer-a barrier layer-an adhesive layer-a material layer, wherein eachof the seal layer and the material layer consists of only apolypropylene elastomer having a melting point of 165° C., each of theadhesive layers consists of only MODIC manufactured by MitsubishiChemical Corporation, and the barrier layer consists of only a cyclicpolyolefin polymer having a glass transition temperature of 136° C.

Moreover, the plastic container according to the present invention forachieving the aforementioned object is molded by heat-sealing theperipheral portions of the multilayered films which comprise aheat-sealable seal layer, a cyclic polyolefin layer, and an outermostlayer wherein the seal layer comprises polypropylene, the cyclicpolyolefin layer comprises a cyclic polyolefin polymer or a cyclicpolyolefin copolymer, and the outermost layer comprises a layercontaining polypropylene, and which further comprises a resincomposition layer comprising a blended product of a propylene polymerand a styrene elastomer, in a state in which the seal layers arelaminated on each other such that they face each other. The plastic filmof the present invention is molded, so that the seal layer thereofbecomes the inner surface thereof. Specifically, the seal layer isallowed to directly come into contact with a liquid-state medicamentwhich is contained in this container.

The plastic container or multilayered film according to the presentinvention preferably comprises a resin composition layer or apolyethylene layer on the surfaces of both sides of the cyclicpolyolefin layer. In addition, for such resin composition layer, a resincomposition having a fusion peak temperature only in a temperature rangefrom 120° C. or higher to 170° C. or lower and also having a heat offusion from 5 J/g or more to 20 J/g or less is preferably used.

The cyclic polyolefin in the cyclic polyolefin layer used for theplastic container or multilayered film according to the presentinvention is preferably a ring-opening polymer hydrogenation product ofdicyclopentadiene or a derivative thereof. Moreover, another preferredembodiment of the cyclic polyolefin is cyclic polyolefin having a glasstransition temperature (Tg) of 80° C. to 120° C. A further preferredembodiment of the cyclic polyolefin is cyclic polyolefin having a meltflow rate (230° C., 21.2 N) value of 1 to 20 (g/10 minutes).

As a seal layer used for the plastic container or multilayered filmaccording to the present invention, polypropylene having a melt flowrate (230° C., 21.2 N) value of 1 to 4 (g/10 minutes) is preferable.Furthermore, another preferred embodiment of the seal layer is a seallayer having a bending elasticity of 400 to 600 MPa. A further preferredembodiment of the seal layer is polypropylene having the maximum fusionpeak temperature of 125° C. to 135° C. A still further preferredembodiment of the seal layer is propylene having the highest fusion peaktemperature of 150° C. to 160° C. The maximum fusion peak temperatureand the highest fusion peak temperature used in the presentspecification will be described. There are cases in which multipleendothermic peaks are observed in differential scanning calorimetry(DSC). The maximum fusion peak temperature means a temperature at whichthe largest endothermic peak is observed, and the highest fusion peaktemperature means a temperature at which the highest temperature peak isobserved in a temperature range in which such endothermic peaks areobserved.

The outermost layer used for the plastic container or multilayered filmaccording to the present invention is preferably polypropylene having amelt flow rate (230° C., 21.2 N) value of 1 to 4 (g/10 minutes). Anotherpreferred embodiment of the outermost layer is polypropylene having abending elasticity of 400 to 600 MPa. A further preferred embodiment ofthe outermost layer is polypropylene having a fusion peak temperature of160° C. to 170° C.

In the present invention, a multilayered film having a tensileelasticity of 300 MPa or less and a plastic container molded using thismultilayered film are preferable.

The plastic container according to the present invention can bepreferably sterilized at 115° C. for 30 minutes or more. In anotherpreferred embodiment, the plastic container according to the presentinvention can be sterilized at 121° C. for 15 minutes or more.

The active ingredient of a liquid-state medicament placed in the plasticcontainer according to the present invention is preferably a pyrazolonederivative represented by the formula (I) as shown below, aphysiologically acceptable salt thereof, a hydrate thereof, or a solvatethereof:

(wherein R¹ represents a hydrogen atom, an aryl, an alkyl containing 1to 5 carbon atoms, or an alkoxycarbonylalkyl containing 3 to 6 carbonatoms in total; R² represents a hydrogen atom, an aryloxy, anarylmercapto, an alkyl containing 1 to 5 carbon atoms, or a hydroxyalkylcontaining 1 to 3 carbon atoms; or R¹ and R² together represent analkylene containing 3 to 5 carbon atoms; R³ represents a hydrogen atom,an alkyl containing 1 to 5 carbon atoms, a cycloalkyl containing 5 to 7carbon atoms, a hydroxyalkyl containing 1 to 3 carbon atoms, a benzyl,naphthyl or phenyl, or a phenyl substituted with 1 to 3 identical ordifferent substituents selected from the group consisting of an alkoxycontaining 1 to 5 carbon atoms, a hydroxyalkyl containing 1 to 3 carbonatoms, an alkoxycarbonyl containing 2 to 5 carbon atoms in total, analkylmercapto containing 1 to 3 carbon atoms, an alkylamino containing 1to 4 carbon atoms, a dialkylamino containing 2 to 8 carbon atoms intotal, a halogen atom, a trifluoromethyl, a carboxyl, a cyano, ahydroxyl group, a nitro, an amino, and an acetamide). In anotherpreferred embodiment, the active ingredient of a liquid-state medicamentis 3-methyl-1-phenyl-2-pyrazolin-5-one.

The plastic container according to the present invention is preferablyin the form of an infusion bag.

Moreover, the plastic container according to the present invention ispreferably placed together with an oxygen absorber into a poorlyair-permeable container.

When the active ingredient of a liquid-state medicament placed in theplastic container according to the present invention is the pyrazolonederivative represented by the above-described formula (I), aphysiologically acceptable salt thereof, a hydrate thereof, or a solventthereof, a reduction percentage in the content of the active ingredientafter the preservation thereof at 60° C. for 4 weeks is preferably 4% orless. On the other hand, a reduction percentage in the content of theactive ingredient after sterilization is preferably 4% or less.

BEST MODE FOR CARRYING OUT THE INVENTION

The plastic container and the multilayered film provided by the presentinvention have a structure in which they comprise at least a cyclicpolyolefin layer and a resin composition layer between an outermostlayer and a seal layer. The disposition is not limited. Preferably, theresin composition layers or the polyethylene layers are disposed on bothsides of the cyclic polyolefin layer. More preferably, the resincomposition layers are disposed on both sides of the cyclic polyolefinlayer. The resin composition layer that can be disposed on the outermostlayer side of this cyclic polyolefin layer may be identical to ordifferent from the resin composition layer that can be disposed on theseal layer side thereof. The same applies to the polyethylene layer.

Polyethylene that constitutes the polyethylene layer used in the presentinvention may be a copolymer of ethylene with α-olefin such aspropylene, 1-butene, 4-methyl-1-pentene or 1-octene, as well as anethylene homopolymer. In addition, the above-mentioned copolymer may beeither a linear or branched copolymer. Moreover, a mixed resin of theethylene homopolymer and the above-mentioned α-olefin may also be used.Furthermore, regardless of whether it is high-density or low-density,such polyethylene can be selected from a wide range of polyethylenes, asappropriate. From the viewpoint of flexibility and transparency, linearlow-density polyethylene is advantageously used.

Specific examples of polyethylene preferably used in the presentinvention include an ethylene homopolymer (product name: HARMOREC(registered trademark)), an α-olefin copolymer (product name: TOUGHMER(registered trademark)), and an ethylene-1-octene copolymer (productname: MORETEC (registered trademark)). A more preferred example ofpolyethylene is a mixed resin of HARMOREC (registered trademark) andTOUGHMER (registered trademark).

The thickness of this polyethylene layer is not particularly limited. Itis preferably from 10 μm or more to 150 μm or less.

A resin composition that constitutes the resin composition layer used inthe present invention preferably has a fusion peak temperature only in atemperature range from 120° C. or higher to 170° C. or lower and alsohas a heat of fusion from 5 J/g or more to 20 J/g or less. This resincomposition plays a role in improving the adhesion between a cyclicpolyolefin polymer or a cyclic polyolefin copolymer and a polyolefinlayer and also in improving the flexibility of the multilayered film asa whole. This resin composition has a fusion peak temperature in atemperature range from 120° C. or higher to 170° C. or lower that isderived from the crystalline component of the resin. If such fusion peaktemperature is lower than 120° C., a multilayered film resistant tosterilization at 121° C. cannot be constituted. On the other hand, ifsuch fusion peak temperature exceeds 170° C., the molding temperature istoo high to produce a multilayered film with good appearance. Moreover,if the heat of fusion is less than 5 J/g, a multilayered film resistantto sterilization at 121° C. cannot be constituted. On the other hand, ifit exceeds 20 J/g, the adhesion with a cyclic polyolefin polymer or acyclic polyolefin copolymer becomes poor, and delamination (delami)easily occurs after completion of the sterilization. As a result, thereis a fear that the appearance becomes deteriorated or desiredpreservability cannot be obtained.

Furthermore, when the resin composition has a fusion peak temperature ina temperature range of lower than 120° C., since a component having suchfusion peak is melted during sterilization, the heat resistance of theresin composition is lost, and as a result, deformation, whitening andthe like occur on the multilayered film. Examples of a resin having afusion peak temperature in a temperature range of lower than 120° C.include high pressure method polyethylene or linear low-densitypolyethylene having a density of 0.93 or less, and an ethylene-α-olefincopolymer having a density of 0.90 or less.

The method for producing the resin composition of the present inventionis not particularly limited, as long as the produced resin compositionsatisfies the above-described conditions, namely, as long as it has afusion peak temperature only in a temperature range from 120° C. orhigher to 170° C. or lower and also has a heat of fusion from 5 J/g ormore to 20 J/g or less. For example, there can be applied a method,which comprises: first producing a crystalline propylene homopolymerhaving a fusion peak temperature in a temperature range from 120° C. orhigher to 170° C. or lower, or a propylene-ethylene copolymer containinga small amount of ethylene (approximately 3% by weight or less) bycontinuous polymerization; and then producing a copolymer consisting ofsubstantially amorphous propylene that does not have a fusion peaktemperature in a temperature range from 120° C. or higher to 170° C. orlower and approximately 10% to 20% by weight of ethylene; so as tototally obtain a resin composition having a heat of fusion from 5 J/g ormore to 20 J/g or less. There can also be applied a method, whichcomprises: producing a crystalline propylene homopolymer having a fusionpeak temperature in a temperature range from 120° C. or higher to 170°C. or lower, or a propylene-ethylene copolymer of propylene and a smallamount of ethylene (approximately 3% by weight or less), and a copolymerof propylene and approximately 10% to 20% by weight of ethylene,separately; and then blending them; so as to totally obtain a resincomposition having a heat of fusion from 5 J/g or more to 20 J/g orless.

The above-described method for producing a resin composition bycontinuous polymerization is disclosed, for example, in JP PatentPublication (Kokai) Nos. 2001-172454 A and 2003-292700 A.

Further, there are produced: a crystalline propylene homopolymer havinga fusion peak temperature in a temperature range from 120° C. or higherto 170° C. or lower, a propylene-ethylene copolymer containing a smallamount of ethylene (approximately 3% by weight or less); a crystallinepropylene homopolymer having a fusion peak temperature in a temperaturerange from 120° C. or higher to 170° C. or lower, or apropylene-ethylene copolymer containing a small amount of ethylene(approximately 3% by weight or less), produced by continuouspolymerization. Thereafter, a copolymer consisting of amorphous orsemi-crystalline propylene that does not have a fusion peak temperaturein a temperature range from 120° C. or higher to 170° C. or lower andapproximately 10% to 20% by weight of ethylene is produced to obtain apropylene polymer composition. A propylene copolymer having a fusionpeak temperature in a temperature range from 120° C. or higher to 170°C. or lower, selected from among the thus obtained propylene polymercompositions, are blended with a styrene elastomer, so as to obtain ablended product.

The above-described styrene elastomer indicates a hydrogenatedderivative of a vinyl aromatic hydrocarbon-conjugated diene blockcopolymer. It is one or two or more types of hydrogenated derivatives ofsuch block copolymer represented by the formula: a(b-a)n, (a-b)n, ora-b-c (wherein (a) represents a polymer block of monovinyl-substitutedaromatic hydrocarbon; (b) represents a random copolymer block of amonovinyl-substituted aromatic hydrocarbon and a conjugated diene, or anelastomeric polymer block of conjugated diene; (c) represents a block ofa monovinyl-substituted aromatic hydrocarbon and a conjugated diene,which is a taper block in which the monovinyl-substituted aromatichydrocarbon is gradually increased; and n represents an integer of 1 to5).

Examples of a monovinyl aromatic hydrocarbon constituting theabove-described polymer block (a), (b) or (c) include styrene,α-methylstyrene, (o-, m-, p-)methylstyrene, 1,3-dimethylstyrene,vinylnaphthalene, and vinylanthracene. Of these, styrene orα-methylstyrene is preferable. As a conjugated diene monomer used in theabove-described polymer block (b) or (c), butadiene and/or isoprene arepreferable. When butadiene is used as a single conjugated diene monomerto form the polymer block (b) or (c), for the purpose of increasingcompatibility with a propylene polymer, after a block copolymer has beenhydrogenated so that a double bond has become saturated, there arepreferably adopted polymerization conditions in which a1,2-microstructure accounts for 50% or more (by weight) of themicrostructure of polybutadiene. The preferred amount of the1,2-microstructure is from 50% by weight to 90% by weight. The amount ofthe polymer block (a) in the hydrogenated block copolymer, or the totalamount of the vinyl aromatic compounds of the polymer block (a) and thepolymer block (c), is generally from 3% to 30% by weight, and preferablyfrom 5% to 20% by weight. When the amount of the polymer block (a) orthe total amount of the vinyl aromatic compounds of the polymer block(a) and the polymer block (c) is less than 3% by weight, the mechanicalstrength of the obtained composition tends to be deteriorated. On theother hand, when the amount of the polymer block (a) or the total amountof the vinyl aromatic compounds of the polymer block (a) and the polymerblock (c) exceeds 30% by weight, the flexibility and transparency of thecomposition tend to be deteriorated.

The weight average molecular weight of a styrene elastomer (ahydrogenated derivative of a vinyl aromatic hydrocarbon-conjugated dieneblock copolymer) is generally 100,000 to 550,000, preferably 150,000 to500,000, and more preferably 200,000 to 450,000, as a value relative topolystyrene measured by gel permeation chromatography. If such weightaverage molecular weight is less than 100,000, rubber elasticity andmechanical strength tend to be deteriorated. On the other hand, if itexceeds 550,000, viscosity becomes high, and molding processabilitytends to be deteriorated.

Examples of the above-described styrene elastomer (a hydrogenatedderivative of a vinyl aromatic hydrocarbon-conjugated diene blockcopolymer) include commercially available products such as “KRATON-G”manufactured by Kraton Polymers, “SEPTON” & “HYBRAR” manufactured byKuraray Co., Ltd., “Toughtech” manufactured by Asahi Kasei Corporation,“Dynaron” manufactured by JSR, and “SIBSTAR” composed of a styrene blockand an isobutylene block obtained by cationic polymerization,manufactured by Kaneka Corporation.

As a resin composition having a fusion peak temperature in a temperaturerange from 120° C. or higher to 170° C. or lower and also having a heatof fusion from 5 J/g or more to 20 J/g or less as obtained above, ZELASMC729 manufactured by Mitsubishi Chemical Corporation is preferable.

The thickness of this resin composition layer is not particularlylimited. It is preferably from 20 μm or more to 120 μm or less, and morepreferably from 20 μm or more to 75 μm or less. Moreover, when resincomposition layers are disposed on both sides of a cyclic polyolefinlayer, the thickness of a resin composition layer on the seal layer sidemay be identical to or different from the thickness of a resincomposition layer on the outermost layer side.

Examples of the cyclic polyolefin polymer or cyclic polyolefin copolymerconstituting the cyclic polyolefin layer used in the present inventioninclude: a copolymer of ethylene and dicyclopentadiene; a copolymer ofethylene and a norbornene compound; a ring-opening polymer of acyclopentadiene derivative; a ring-opening copolymer of variouscyclopentadiene derivatives; and a hydrogenation product thereof. Ofthese, a hydrogenation product of a copolymer of ethylene and anorbornene compound, or a hydrogenation product of a ring-opening(co)polymer of one or more types of cyclopentadiene derivatives ispreferably used. A ring-opening polymer hydrogenation product ofdicyclopentadiene or a derivative thereof is more preferable.

The above-described resin includes: a polymer having a repeating unitrepresented by the formula (1) as shown below and a repeating unitrepresented by the formula (1′) as shown below; and a polymer having arepeating unit represented by the formula (2) as shown below.

(wherein, in formulae (1) and (1′), each of Ra, Ra′, Rb and Rb′identically or differently represents a hydrogen, a hydrocarbon residue,or a polar group such as a halogen, an ester, a nitrile or a pyridyl;Ra, Ra′, Rb and Rb′ may bind to one another to form a ring; each of mand m′ represents an integer of 1 or greater; and each of n and n′represents an integer of 0 or 1 or greater).

(wherein, in formula (2), each of Rc and Rd identically or differentlyrepresents a hydrogen, a hydrocarbon residue, or a polar group such as ahalogen, an ester, a nitrile or a pyridyl; R³ and R⁴ may bind to eachother to form a ring; each of x and z represents an integer of 1 orgreater; and y represents an integer of 0 or 1 or greater).

The polymer having the repeating units represented by the formulae (1)and (1′) is produced by polymerizing one or two or more types ofmonomers according to a known ring-opening polymerization method, orfurther by hydrogenating the thus obtained ring-opening polymeraccording to an ordinary method. Specific examples of such polymerinclude “ZEONOA (product name; registered trademark)” as a hydrogenatedpolymer manufactured by Zeon Corporation, and “ARTON (product name;registered trademark)” manufactured by Japan Synthetic Rubber Co., Ltd.The polymer having the structural unit represented by the formula (2) isproduced by subjecting one or two or more types of norbornene monomersused as monomers and ethylene to addition copolymerization according toa known method, or further by hydrogenating the obtained productaccording to an ordinary method. Specific examples of such polymerinclude “APEL (product name; registered trademark)” manufactured byMitsui Chemicals, Inc., and “TOPAS (product name; registered trademark)”manufactured by Polyplastics Co., Ltd.

Preferred examples of the cyclic polyolefin polymer or cyclic polyolefincopolymer used in the present invention include “ZEONOA (registeredtrademark)” and “TOPAS (registered trademark).”

Among the above-exemplified resins containing the above-describedpolymers having the structural units represented by the formulae (1) and(1′) and the formula (2), the hydrogenation products thereof are allsaturated polymers. Thus, the hydrogenation products are excellent interms of heat resistance, transparency and stability, as well as agas-shielding property and a moisture-shielding property. The cyclicpolyolefin polymer used in the present invention has a glass transitiontemperature (T_(g)) of preferably 70° C. or higher, and more preferably80° C. to 120° C. Moreover, the range of the molecular weight of thepresent cyclic polyolefin polymer is preferably 10,000 to 100,000, andmore preferably 20,000 to 50,000, relative to a number average molecularweight <Mn> measured by gel permeation chromatography (GPC) usingcyclohexane as a solvent. Furthermore, from another viewpoint, the meltflow rate (230° C., 21.2 N) value of the present cyclic polyolefinpolymer is preferably 1 to 20 (g/10 minutes). When an unsaturated bondremaining in the molecular chain of cyclic polyolefin is saturated byhydrogenation, the hydrogenation rate is preferably 90% or more, morepreferably 95% or more, and particularly preferably 99% or more.

The cyclic polyolefin polymer or the cyclic polyolefin copolymer may beused in the state of a single layer, or may also be used as a mixedresin formed by mixing it with another resin. When the cyclic polyolefinpolymer or the cyclic polyolefin copolymer is used as a mixed resin, ifthe content of the cyclic polyolefin polymer or cyclic polyolefincopolymer in the mixed resin is less than 60% by weight, the effect ofpreventing the adsorption of an agent is decreased. On the other hand,if the content of the cyclic polyolefin in the mixed resin exceeds 95%by weight, the flexibility of a multilayered film as a whole isdecreased. Accordingly, when the cyclic polyolefin polymer or cyclicpolyolefin copolymer is used in the form of a mixed resin, the contentof the cyclic polyolefin polymer or cyclic polyolefin copolymer isdesirably from 60% by weight or more to 95% by weight or less.

Examples of a resin to be mixed with the cyclic polyolefin polymer orcyclic polyolefin copolymer include polyethylene, polypropylene, poly1-butene, poly 4-methyl-1-pentene, an ethylene-propylene copolymer, amixture of polypropylene and polyethylene or polybutene, a partiallycross-linked product of the aforementioned polyolefin, an ethylene-vinylacetate copolymer, an ethylene-(meth)acrylic acid ester copolymer, anethylene-(meth)acrylic acid copolymer, and an ethylene-maleic anhydridecopolymer. Of these, preferred examples of such resin include anethylene homopolymer (product name: HARMOREC (registered trademark)), anα-olefin copolymer (product name: TOUGHMER (registered trademark)), andan ethylene-1-octene copolymer (product name: MORETEC (registeredtrademark)).

The thickness of the cyclic polyolefin layer is determined within theaforementioned range, while taking into consideration the balancebetween the effect of preventing the adsorption of an agent and theflexibility of a multilayered film as a whole. If the thickness of thecyclic polyolefin layer is less than 10 μm, the effect of preventing theadsorption of an agent is decreased. On the other hand, if the thicknessexceeds 80 μm, the flexibility of a multilayered film as a whole isdecreased. The particularly preferred range of the thickness of thecyclic polyolefin layer can be from 10 μm to 50 μm. More preferably, thethickness of the cyclic polyolefin layer can be from 10 μm to 30 μm.

As polypropylene constituting the seal layer used in the presentinvention, there can be used not only a propylene homopolymer, but alsoa copolymer produced by copolymerizing propylene with a small amount(preferably 10% by weight or less) of α-olefin such as ethylene or1-butene, a copolymer produced by multistage polymerization of propylenewith α-olefin and the like as disclosed, for example, in JP PatentPublication (Kokai) No. 2001-226435 A. Among others, in order toalleviate the rigidness of the cyclic polyolefin layer and to improvethe flexibility of the multilayered film, polypropylene of a relativelyflexible grade, having a bending elasticity of 400 to 600 MPa, which hasbeen commonly used as a medical container, is preferably used. Moreover,from another viewpoint, polypropylene having a melt flow rate (230° C.,21.2 N) value of 1 to 4 (g/10 minutes) is preferably used. A specificexample of the polypropylene that can be used in the present inventionis ZELAS (registered trademark) manufactured by Mitsubishi ChemicalCorporation. In particular, ZELAS MC607 having a fusion peak temperaturein a temperature range from 125° C. to 135° C. is preferably used. Thethickness of the seal layer is not particularly limited. It ispreferably from 20 to 120 μm.

A layer comprising polypropylene constituting the outermost layer usedin the present invention may be constituted, not only with a propylenehomopolymer, but also with a copolymer produced by copolymerizingpropylene with a small amount (preferably 10% by weight or less) ofα-olefin such as ethylene or 1-butene, a copolymer produced bymultistage polymerization of propylene with α-olefin as disclosed, forexample, in JP Patent Publication (Kokai) No. 2001-226435 and the like.Moreover, a compound of such homopolymer or copolymer with anotherpolyolefin or resin may also be used. Among others, in order toalleviate the rigidness of the cyclic polyolefin layer and to improvethe flexibility of a multilayered film, polypropylene of a relativelyflexible grade, having a bending elasticity of 400 to 600 MPa, which hasbeen commonly used as a medical container, is preferably used.Furthermore, from another viewpoint, the melt flow rate (230° C., 21.2N) value of the outermost layer is preferably set at 1 to 4 (g/10minutes). A specific example of the polypropylene constituting theoutermost layer that can be preferably used in the present invention isZELAS (registered trademark) manufactured by Mitsubishi ChemicalCorporation. In particular, ZELAS MC715 having a fusion peak temperaturein a temperature range from 160° C. to 170° C. is preferably used. Thethickness of the outermost layer is not particularly limited. It ispreferably from 20 to 100 μm.

Hence, a layer containing polypropylene having a high fusion peaktemperature is disposed as an outermost layer, and a polypropylene layerhaving a relatively low fusion peak temperature is disposed as a seallayer, so that the heat-sealing properties of a multilayered filmcontaining a cyclic polyolefin layer are significantly improved, therebyproducing a practical container.

Further, from the viewpoint of shock resistance, handling ability duringthe filling of the container with a medicament, and the moldability ofthe container, the plastic container and multilayered film of thepresent invention obtained with the above-described structure desirablyhas a tensile elasticity of 300 MPa or less.

The active ingredient of a liquid-state medicament that can be filledinto the plastic container provided by the present invention is notlimited. Preferred examples of such active ingredient include thepyrazolone derivative represented by the formula (I) defined in thepresent specification, a physiologically acceptable salt thereof, ahydrate thereof, and a solvate thereof.

The compound represented by the formula (I) may also have a structurerepresented by general formula (I′) or (I″) as shown below, as a resultof tautomerism. As a matter of convenience, a tautomer is shown by theformula (I) in the present specification. However, the presence of thefollowing tautomers is obvious to persons skilled in the art.

In the formula (I), the aryl group represented by R¹ may be either amonocyclic or polycyclic aryl group. Examples of such aryl groupinclude: phenyl groups; naphthyl groups; alkyl groups such as a methylgroup and a butyl group; alkoxy groups such as a methoxy group and abutoxy group; halogen atoms such as a chlorine atom; and phenyl groupssubstituted with substituents such as a hydroxyl group. The same appliesto aryl portions in other substituents (an aryloxy group, etc.) havingsuch aryl portions.

The alkyl group containing 1 to 5 carbon atoms represented by each ofR¹, R² and R³ may be either a linear or branched alkyl group. Examplesof such alkyl group include a methyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, an isobutyl group, a sec-butylgroup, a tert-butyl group, and a pentyl group. The same applies to analkyl portion in another substituent (an alkoxycarbonylalkyl group)having such alkyl portion.

Examples of the alkoxycarbonylalkyl group containing 3 to 6 carbon atomsin total represented by R¹ include a methoxycarbonylmethyl group, anethoxycarbonylmethyl group, a propoxycarbonylmethyl group, amethoxycarbonylethyl group, and a methoxycarbonylpropyl group.

Examples of the alkylene group containing 3 to 5 carbon atomsrepresented by each of R¹ and R² include a trimethylene group, atetramethylene group, a pentamethylene group, a methyltrimethylenegroup, an ethyltrimethylene group, a dimethyltrimethylene group, and amethyltetramethylene group.

Examples of the aryloxy group represented by R² include ap-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxygroup, and a p-hydroxyphenoxy group. Examples of the arylmercapto groupinclude a phenylmercapto group, a p-methylphenylmercapto group, ap-methoxyphenylmercapto group, a p-chlorophenylmercapto group, and ap-hydroxyphenylmercapto group.

Examples of the hydroxyalkyl group containing 1 to 3 carbon atomsrepresented by each of R² and R³ include a hydroxymethyl group, a2-hydroxyethyl group, and a 3-hydroxypropyl group. Examples of thecycloalkyl group containing 5 to 7 carbon atoms represented by R³include a cyclopentyl group, a cyclohexyl group, and a cycloheptylgroup.

Examples of the alkoxy group containing 1 to 5 carbon atoms as asubstituent of the phenyl group represented by R³ include a methoxygroup, an ethoxy group, a propoxy group, an isopropoxy group, a butoxygroup, and a pentyloxy group. Examples of the alkoxycarbonyl groupcontaining 2 to 5 carbon atoms in total include a methoxycarbonyl group,an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonylgroup. Examples of the alkylmercapto group containing 1 to 3 carbonatoms include a methylmercapto group, an ethylmercapto group, and apropylmercapto group. Examples of the alkylamino group containing 1 to 4carbon atoms include a methylamino group, an ethylamino group, apropylamino group, and a butylamino group. Examples of the dialkylaminogroup containing 2 to 8 carbon atoms in total include a dimethylaminogroup, a diethylamino group, a dipropylamino group, and a dibutylaminogroup.

A preferably used compound (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.

The compounds represented by the formula (I) are all known compounds.These compounds can be easily synthesized by persons skilled in the artaccording to the method described in JP Patent Publication (Kokoku) No.5-31523 B (1993), and the like.

When the plastic container provided by the present invention is filledwith a solution comprising, as an active ingredient, the pyrazolonederivative represented by the above-described formula (I), aphysiologically acceptable salt thereof, a hydrate thereof, or a solventthereof (hereinafter generically referred to as a “pyrazolonederivative,” at times), for example, when an infusion bag is prepared byfilling the plastic container with such agent, the pyrazolone derivativeis dissolved in a solvent (for example, an infusion solution, etc.), toa concentration from approximately 0.06 mg/mL or higher to approximately2 mg/mL or lower, preferably from approximately 0.1 mg/mL or higher toapproximately 0.6 mg/mL or lower, and more preferably approximately 0.3mg/mL. Thereafter, a pH adjuster is added to the solution, as desired,so as to adjust the pH of the solution. Thereafter, other additives arefurther added thereto, as desired, so as to prepare an agent filled inthe infusion bag.

In order to prepare a liquid-state medicament to be placed in theplastic container of the present invention, all types of ingredients maybe used, in addition to the active ingredient, as long as they arecommonly used as medicaments. For example, one or two or more types ofingredients arbitrarily selected from among electrolytes, sugars,vitamins, protein amino acids, etc., which are dissolved in any givenconcentrations in water (for example, distilled water for injection,etc.) may be used. An example of such electrolyte is sodium chloride.These arbitrary ingredients may be used in any given concentration,singly or in combination of two or more types. A preferred example issodium chloride or the like that has been dissolved in any givenconcentration in water (for example, distilled water for injection,etc.). In the case of sodium chloride, the content of this ingredient ispreferably equivalent to that of a normal saline, namely, approximately0.9% (W/V). Other than this ingredient, a pH adjuster that is commonlyused as a pH adjuster for injection may be used without particularlimitations.

The types of other additives that can be used to prepare theliquid-state medicament are not particularly limited, as long as theyare commonly used as additives for injections. In the present invention,other preferred additives include pharmaceutical additives described in“Iyakuhin Tenkabutsu Jiten (Pharmaceutical Additive Dictionary),” YakujiNippo 2000 (edited by the Japan Pharmaceutical Excipients Council), andthe like. In general, these additives are mixed at ratios commonlyapplied to injections. In addition, these additives may be separated,for example, into a stabilizer, a surfactant, a buffer, a solubilizingagent, an antioxidant, an antifoaming agent, an isotonizing agent, anemulsifier, a suspending agent, a preservative, a soothing agent, aresolvent, a solubilization aid, and the like, and may be then used.These additive may be used in combination of two or more ingredients, asdesired.

The form of the plastic container of the present invention is notparticularly limited, as long as it is hermetically sealable and is ableto maintain the sterility of the content. In general, containers such asan infusion bag, a syringe, an ampule and a vial, which are used tocontain an injection solution, are preferable. Of these, an infusion bagis particularly preferable. Moreover, in order to confirm the presenceor absence of the generation of insoluble foreign matters, thesecontainers are preferably transparent and colorless. However, an opaque,colored container may also be used.

When a liquid-state medicament is placed in the plastic containerprovided by the present invention, the plastic container can be producedby filling it with the liquid-state medicament and then hermeticallysealing it. Moreover, a sterilization operation is carried out on theplastic container in any given process, so as to produce a plasticcontainer maintaining sterility. Furthermore, before filling thecontainer with the medicament, the agent solution may be filtrated witha dust-proof filter (for example, a 0.45-μm methylcellulose membrane, a0.45-μm nylon 66 membrane, a 0.45-μm polyvinylidene fluoride membrane,etc.), as desired. Specific methods for sterilizing the plasticcontainer of the present invention include a hot water immersionsterilization method, a hot water shower sterilization method, and ahigh-pressure steam sterilization (autoclave) method. Such hot waterimmersion sterilization method, hot water shower sterilization method,and high-pressure steam sterilization method are carried out, forexample, after the agent solution has been prepared and has been thenfilled into the plastic container of the present invention. Thehigh-pressure steam sterilization is preferably carried out, forexample, under conditions of a temperature of 100° C. to 125° C. for 5to 40 minutes. The plastic container of the present invention issterilized, preferably at 115° C. for 30 minutes or longer, and morepreferably 121° C. for 15 minutes or longer.

The plastic container and multilayered film provided by the presentinvention is desirably composed of five or more layers. Specifically, anoutermost layer-a resin composition layer-a cyclic polyolefin layer-aresin composition layer-a seal layer is desirably used as a base. Byadopting such structure, it becomes possible to sterilize the plasticcontainer of the present invention at 121° C. for 15 minutes or longer,and as, a result, a plastic container that has flexibility and highshock resistance and can be easily filled with an agent solution can beproduced. Moreover, it is also possible to add any given resin layersbetween any given layers of the outermost layer-resin compositionlayer-cyclic polyolefin layer-resin composition layer-seal layer. Theany given resin layers added herein include polyolefins such aspolypropylene, polyamides, polyesters such as polyethylene terephthalateor polybutylene terephthalate, and ethylene-vinyl alcohol copolymers.Specifically, polyolefins prepared by grafting these polar materialswith α,β unsaturated carboxylic acids having adhesiveness therewith,copolymers of carboxylic acids and ethylenes, etc. may be used. Ofthese, preferred examples of the resin layer include the resincomposition layer as described above in the present specification, apolypropylene layer, and a layer containing polypropylene. In order todetermine the structure of layers, it is desired to adjust the layerstructure, such that the tensile elasticity of the obtained multilayeredfilm can be 300 MPa or less.

When the form of the plastic container provided by the present inventionis an infusion bag, it can be produced by sealing the peripheralportions of the multilayered films provided by the present inventionaccording to an ordinary method and molding it into the form of a bag.The thickness of the multilayered film is preferably 500 μm or less, andparticularly preferably 200 to 300 μm.

The multilayered film provided by the present invention can be producedby applying various types of conventionally known methods such as aco-extrusion inflation method or a co-extrusion T-die method.

The plastic container of the present invention may be wrapped with alight-shielding material to suppress the permeability of a light with aspecific wavelength. The type of a wrapping material used in suchwrapping is not particularly limited, as long as it is a commonly usedlight-shielding wrapping material. Specifically, a bag made of amaterial for suppressing the permeability of a light with a specificwavelength, a bag made of a light-shielding material such as plastic oraluminum, a shrink wrapping material (for example, a shrink label, etc.)using light-shielding plastic, a blister wrapping material, and the likemay be used. By the combined use of these light-shielding materials,their light-shielding properties can be further enhanced.

Furthermore, the plastic container of the present invention may beplaced in a poorly air-permeable container. The type of such poorlyair-permeable container is not particularly limited, as long as it isproduced from a commonly used, poorly air-permeable material.Specifically, it is adequate if such container hardly gives passage tooxygen or nitrogen. Examples of such poorly air-permeable containerinclude an aluminum container and a PET film container formed by silicaevaporation. Furthermore, an oxygen absorber may also be placed in suchpoorly air-permeable container.

EXAMPLES

The present invention will be more specifically described in thefollowing production example, test example, and examples. However, theseexamples are not intended to limit the scope of the present invention.

Production Example of Infusion Bag

Films having the structures shown in Table 1 were produced using awater-cooled type inflation device capable of molding 6 types of6-layered films. Thereafter, a polyethylene or polypropylene port wasdeposited on each film, so as to mold a 100-mL infusion bag on which apolyethylene or polypropylene port was deposited. That is to say, theperipheral portions of the multilayered films shown in Table 1 wereheat-sealed in a state in which the seal layers were laminated on eachother such that they faced each other, so as to produce each infusionbag. In Table 1, films A01, A03, C01 and C02 are the examples of thepresent invention, and films A02, A04, A05, B01, B02 and B03 are thereference examples of the present invention.

TABLE 1 Film composition Outer layer 1 2 3 4 (Barrier layer) 5 6 innerlayer A01 ZELAS MC715 ZELAS MC717 TOPAS 9506F-04 ZELAS MC717 ZELAS MC60730 μm 70 μm 10 μm 60 μm 60 μm A02 ZELAS MC715 ZELAS MC717 TOPAS 9506F-04ZELAS MC717 MORETEC 30 μm 70 μm 10 μm 60 μm 0248Z 60 μm A03 ZELAS MC715ZELAS MC717 TOPAS 9506F-04/ ZELAS MC717 ZELAS MC607 30 μm 70 μm MORETEC0168N 60 μm 50 μm 20 μm A04 MORETEC 0168N HARMOREC NV325N/ TOPAS9506F-04 ZELAS MC717 ZELAS MC607 30 μm TOUGHMER 04085 /MORETEC 0168N 60μm 50 μm 70 μm 20 μm A05 MORETEC 0168N HARMOREC NV325N/ ZEONOA 1060RZELAS MC717 ZELAS MC607 30 μm TOUGHMER 04085 10 μm 60 μm 60 μm 70 μm B01ZELAS MC715 TOPAS 8007 ZELAS MC607 70 μm 20 μm 110 μm B02 ZELAS MC715ZEONOA 1060R ZELAS MC607 70 μm 20 μm 110 μm B03 ZELAS MC715 ZEONOA 1060RZELAS MC607 70 μm 30 μm 100 μm C01 ZELAS MC715 ZELAS MC717 ZELAS MC729ZEONOA 1060R ZELAS MC729 ZELAS MC607 20 μm 20 μm 30 μm 15 μm 75 μm 40 μmC02 ZELAS MC715 ZELAS MC717 ZELAS MC729 ZEONOA 1060R ZELAS MC729 ZELASMC607 20 μm 35 μm 45 μm 15 μm 75 μm 40 μm 2 3 Comparative ZELASRT-267A-1 ZELAS MC717 ZELAS 7023 Example 1 40 μm 120 μm 40 μm

In the table, ZELAS (registered trademark) is an olefin(homopolypropylene) thermoplastic elastomer distributed by MitsubishiChemical Corporation. ZELAS MC717 and ZELAS MC729 are resin compositionscomprising blended products of propylene polymers and styreneelastomers. TOPAS (registered trademark) is a cyclic polyolefincopolymer distributed by Polyplastics Co., Ltd. MORETEC (registeredtrademark) is a linear low-density polyethylene C8 copolymer produced bycopolymerizing ethylene and 1-octene, which is distributed by PrimePolymer Co., Ltd. HARMOREC (registered trademark) is polyethylenedistributed by Japan Polyethylene Corporation. TOUGHMER (registeredtrademark) is an α-olefin copolymer distributed by Mitsui Chemicals,Inc. ZEONOA (registered trademark) is a cyclic polyolefin polymerdistributed by Zeon Corporation.

Example 1

A solution obtained by diluting commercially available Radicut(registered trademark) injection 30 mg (manufactured and distributed byMitsubishi Tanabe Pharma Corporation) with 100 mL of a normal saline wasfilled into an infusion bag formed with each of various types of filmsA01 to A05 and Comparative Example 1 shown in Table 1, and it was thensterilized (115° C., 30 minutes). The content of a main component(Edaravone) was measured before and after the sterilization. The resultsare shown in Table 2. In the case of using a film comprising a cyclicpolyolefin polymer or a cyclic polyolefin copolymer as a barrier layer,a significant reduction in the content of the component was not observedafter the sterilization. On the other hand, in the case of using a filmconstituted only with polypropylene (ZELAS (registered trademark)RT-267A-1, MC717, 7023), a reduction in the content of the component wasobserved after sterilization.

TABLE 2 Medicament adsorption on bag during sterilization in case ofusing COP or COC as barrier layer After Reduction rate After fillingsterilization in content Film A01 101.1 99.1 2.0 Film A03 101.1 98.3 2.8Comparative 102.7 98.4 4.3 Example 1

Test Example 1

A solution obtained by diluting commercially available Radicut(registered trademark) injection 30 mg (manufactured and distributed byMitsubishi Tanabe Pharma Corporation) with 100 mL of a normal saline wasfilled into an infusion bag formed with each of various types of filmsA05 and B01 to B03 shown in Table 1, and it was then sterilized (115°C., 30 minutes). The content of a main component (Edaravone) wasmeasured before and after the sterilization. The results are shown inTable 3. Films comprising a cyclic polyolefin polymer or a cyclicpolyolefin copolymer as a barrier layer were able to suppress theadsorption of the component during the sterilization at almost samelevels. If the thickness of such cyclic polyolefin polymer was 10 μm ormore, it sufficiently exhibited its functions.

TABLE 3 After filling After sterilization Reduction rate in contentDifference in medicament adsorption on bag in case of using COP or COCas barrier layer Film B01 103.1 100.2 2.9 Film B02 103.1 101.7 1.4Influence of thickness of COP on medicament adsorption Film A05 97.996.1 1.8 Film B02 97.9 97.7 0.2 Film B03 97.9 97.3 0.6

Example 2

A solution obtained by diluting commercially available Radicut(registered trademark) injection 30 mg (manufactured and distributed byMitsubishi Tanabe Pharma Corporation) with 100 mL of a normal saline wasfilled into an infusion bag formed with each of various types of filmsof C01, C02 and Comparative Example 1 shown in Table 1, and it was thensterilized (115° C., 30 minutes). Thereafter, a severe test (60° C., 4weeks) was carried out on each sample wrapped with a second wrappingmaterial containing AGELESS as an oxygen absorber and having asuppressed gas permeability, which had been formed by silicaevaporation. As shown in Table 4, in the case of the bag of ComparativeExample 1, a reduction in the content of the component was observed overtime. However, such reduction in the content of the component was notobserved in the case of the bags of C01 and C02.

TABLE 4 Severe stability test of bags containing COP as barrier layers(60° C.) After After filling sterilization Week 1 Week 2 Week 4 Film C0197.9 96.4 96.2 97.3 98.2 Film C02 97.9 96.1 96.7 96.9 97.5 Comparative102.7 98.4 91.0 90.9 Example 1

In the table, in the case of films C01 and C02, the content of Edaravoneafter 4 weeks have passed is higher than the content of Edaravone aftercompletion of the sterilization. This is because the solvent (water) inthe bag was evaporated to outside of the bag during the storage at 60°C.

INDUSTRIAL APPLICABILITY

According to the present invention, a plastic container suitable forcontaining a liquid-state medicament and a multilayered film used toproduce this container can be provided. The plastic container and themultilayered film obtained by the present invention are able to suppressa reduction in the content of the active ingredient of a medicamentcontained therein, do not cause delamination due to high-pressure steamsterilization and long-term conservation, and are excellent in terms ofshock resistance, handling ability during the filling of the containerwith a medicament, and the moldability and transparency of thecontainer.

1-19. (canceled)
 20. A pharmaceutical formulation in a unit dosage formcomprising 3-methyl-1-phenyl-2-pyrazolin-5-one; wherein the unit dosageform is a solution stored in a plastic container, and wherein thecontainer comprises: a multilayered film having six or more layers,wherein the six or more layers are: an innermost heat-sealable seallayer consisting essentially of polypropylene, a first resin compositionlayer disposed on the innermost heat-sealable seal layer consistingessentially of a resin composition comprising a blended product of apropylene polymer and a styrene elastomer, a cyclic polyolefin barrierlayer disposed on the first resin composition layer consisting of apolymer consisting of repeating units represented by the formula (1) andrepeating units represented by the formula (1′):

wherein each of Ra, Ra′, Rb and Rb′, identically or differently,represents a hydrogen, a hydrocarbon residue, a halogen, an ester, anitrile or a pyridyl; or Ra and Rb may bind to one another to form aring; or Ra′ and Rb′ may bind to one another to form a ring; each of mand m′ represents an integer of 1 or greater; and each of n and n′represents an integer of 0 or 1 or greater, two or more additional resincomposition layers disposed on the cyclic polyolefin barrier layerconsisting essentially of a resin composition comprising a blendedproduct of a propylene polymer and a styrene elastomer, and an outermostlayer disposed on the additional resin composition layers consistingessentially of a polypropylene layer; wherein the plastic container ismolded by heat sealing peripheral portions of the multilayered films.21. The pharmaceutical formulation in a unit dosage form according toclaim 20, wherein the cyclic polyolefin barrier layer has a glasstransition temperature (Tg) of 80° C. to 120° C.
 22. The pharmaceuticalformulation in a unit dosage form according to claim 20, wherein themelt flow rate (230° C., 21.2 N) value of the cyclic polyolefin barrierlayer is 1 to 20 (g/10 minutes).
 23. The pharmaceutical formulation in aunit dosage form according to claim 22, wherein the melt flow rate (230°C., 21.2 N) value of the seal layer and/or the outermost layer is 1 to 4(g/10 minutes).
 24. The pharmaceutical formulation in a unit dosage formaccording to claim 20, wherein the maximum fusion peak temperature ofthe seal layer is 125° C. to 135° C.
 25. The pharmaceutical formulationin a unit dosage form according to claim 24, wherein the highest fusionpeak temperature of the seal layer is 150° C. to 160° C.
 26. Thepharmaceutical formulation in a unit dosage form according to claim 20,wherein the fusion peak temperature of the outermost layer is 160° C. to170° C.
 27. The pharmaceutical formulation in a unit dosage formaccording to claim 20, wherein the plastic container can be sterilizedat 115° C. for 30 minutes or more.
 28. The pharmaceutical formulation ina unit dosage form according to claim 20, wherein the plastic containercan be sterilized at 121° C. for 15 minutes or more.
 29. Thepharmaceutical formulation in a unit dosage form according to claim 20,wherein the plastic container is in the form of an infusion bag.
 30. Thepharmaceutical formulation in a unit dosage form according to claim 29,wherein the plastic container can be sterilized at 115° C. for 30minutes or more.
 31. The pharmaceutical formulation in a unit dosageform according to claim 20, wherein the unit dosage form comprises 30 mgof 3-methyl-1-phenyl-2-pyrazolin-5-one.
 32. The pharmaceuticalformulation in a unit dosage form according to claim 20, wherein the3-methyl-1-phenyl-2-pyrazolin-5-one is contained in a concentration of0.06 mg/mL or higher to 2 mg/mL or lower.
 33. The pharmaceuticalformulation in a unit dosage form according to claim 32, wherein the3-methyl-1-phenyl-2-pyrazolin-5-one is contained in a concentration of0.1 mg/mL or higher to 0.6 mg/mL or lower.
 34. The pharmaceuticalformulation in a unit dosage form according to claim 33, wherein the3-methyl-1-phenyl-2-pyrazolin-5-one is contained in a concentration ofabout 0.3 mg/mL.
 35. The pharmaceutical formulation in a unit dosageform according to claim 20, wherein the3-methyl-1-phenyl-2-pyrazolin-5-one is contained in an injectionsolution.
 36. The pharmaceutical formulation in a unit dosage formaccording to claim 35, wherein the injection solution is saline.